Premium
In vitro assessment of stereoselective hepatic metabolism of disopyramide in humans: Comparison with in vivo data
Author(s) -
Le Corre Pascal,
Ratanasavanh Damrong,
Chevanne François,
Gibassier Denis,
Sado Pierre,
Le Verge Roger,
Guillouzo André
Publication year - 1991
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530030505
Subject(s) - chemistry , in vivo , stereoselectivity , in vitro , metabolism , disopyramide , biochemistry , pharmacology , combinatorial chemistry , medicine , microbiology and biotechnology , catalysis , biology
Metabolism of disopyramide (DP) enantiomers has been investigated in primary cultures of adult human hepatocytes. Results were compared with in vivo data obtained from a previous pharmacokinetic study (Le Corre et al. Drug Metab. Dispos. 16:858–864 1988). Metabolism of DP enantiomers as a function of incubation time showed constant velocity over time. The intracellular/extracellular distribution of both DP and mono‐ N ‐desisopropyldisopyramide did not appear to be stereoselective. Metabolism of DP enantiomers as a function of substrate concentration followed a first order kinetics. The average fractions of (‐)‐(R)‐DP and (+)‐(S)‐DP metabolized in vitro (4.7 ± 2.7 and 7.1 ± 4.2%, respectively, n = 4) were about 5‐fold lower than the fractions metabolized in vivo (26.0 ± 6.0 and 40.2 ± 8.8%, respectively, n = 6). The stereoselective index [(+)‐(S)/(‐)‐(R)] of the N‐dealkylation pathway obtained in vitro (1.51 ± 0.11, n = 4) was very close to the one obtained in vivo (1.55 ± 0.10, n = 6). These results highlight the interest of hepatocyte cultures in the evaluation of drug metabolism and especially in the assessment of stereoselectivity.